There is good evidence that the antitumor agent hexamethylmelamine (HMM) undergoes oxidative activation which might occur in the liver and/or extrahepatically. The hepatic microsomal N-methylmelamine metabolizing enzymes were investigated in mice and exhibited different affinities for different melamine derivatives. The apparent K(m) values are 0.09 mM for HMM, 0.23 mM for pentamethylmelamine, 0.91 mM for 2,2,4,6-tetramethylmelamine and 1.7 mM for trimethylmelamine. HMM inhibited its own mechanism in vitro at substrate concentrations >0.5 mM. Its hepatic microsomal N-methylation rate was reduced when the mice were pretreated with hepatic glutathione depleting agent methyliodide. Injection of hexaethylmelamine, a derivative of HMM without antineoplastic properties against the M5076 sarcoma in mice, lead to plasma concentrations of drug and metabolite pentaethylmelamine which were only a fraction of the drug and metabolite levels achieved after a similar dose of HMM.
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